Amylin is a recently discovered peptide which has marked effects on carbohydrate metabolism in vitro and in vivo, including the ability to inhibit the uptake of glucose and to suppress the synthesis of glycogen in isolated skeletal muscle. Cooper, G. J. S. et al., Proc. Natl. Acad. Sci. USA 85:7763-7766 (1988). A defect in amylin homeostasis is believed to contribute to insulin resistance and the development of Type 2 diabetes mellitus, Cooper, G. J. S. et al., Biochim. Biophys. Acta. 1014:247-258 (1989), as well as other metabolic disorders.
Amylin is a 37 amino acid peptide that shows about 46% identity in amino acid sequence on comparison with the calcitonin gene-related peptides (CGRPs). Cooper, G. J. S. et al., Progress in Growth Factor Research 1:99-105 (1989). CGRP shares limited sequence identity, about 30%, with calcitonin and common parentage in that alternate processing of a primary mRNA transcript leads to the generation of the two distinct peptides. Amara, S. G. et al., Science 229:1094-1097 (1985).
Compounds that inhibit the effects of amylin and its agonists (i.e., mimics of one or more of the effects of amylin) are referred to as amylin "antagonists." Amylin antagonist compounds and uses therefor are the subject of commonly owned U.S. application Ser. No. 07/794,288, filed Nov. 19, 1992, for "Novel Amylin Antagonist Peptides and Uses Therefor," the disclosure of which is hereby incorporated by reference.
Amylin antagonist peptides may or may not be selective for amylin receptors. More selective antagonists may exhibit less side effects than those which might be associated with more non-selective antagonists. For example, non-selective amylin antagonists may bind to calcitonin or CGRP receptors and could thereby produce unwanted effects related to calcium homeostasis or blood pressure regulation. It is an object of the invention to provide further novel and potent amylin antagonists, including antagonists which are more selective for amylin receptors than for calcitonin and CGRP receptors.